Journal Article

Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates

Johnson, Steven, Prosser, Beverly E., Zhang, Qian, Tang, Christoph M., Lea, Susan M., Kugelberg, Elisabeth, Schneider, Muriel C., Sim, Robert B., Caesar, Joseph J. E., Deane, Janet E., Quoraishi, Sadik, Lovett, Janet E., Li, Su, Roversi, Pietro

2009

Overview

A mimic in meningitis The human pathogen Neisseria meningitidis , a leading cause of bacterial meningitis and septic shock, possesses a surface protein, factor H binding protein or fHbp, that binds to host complement regulator factor H, thereby interfering with the immune response. Now the structure of the complex between human complement regulator factor H and fHbp has been determined. It reveals that the bacterial protein binds factor H by mimicking the glycosaminoglycans that occur naturally on host endothelial cells where they recruit factor H to prevent complement-mediated damage of the vascular tree. This work has important implications for the development of vaccines and therapeutics to counter meningococcal disease. Neisseria meningitidis possesses a surface protein called fHbp that binds to the complement regulator factor H, thereby interfering with the host immune response. Now the structure of N. meningitidis fHbp bound to factor H is presented, revealing the molecular interactions between these two molecules. The complement system is an essential component of the innate and acquired immune system 1 , and consists of a series of proteolytic cascades that are initiated by the presence of microorganisms. In health, activation of complement is precisely controlled through membrane-bound and soluble plasma-regulatory proteins including complement factor H (fH; ref. 2 ), a 155 kDa protein composed of 20 domains (termed complement control protein repeats). Many pathogens have evolved the ability to avoid immune-killing by recruiting host complement regulators 3 and several pathogens have adapted to avoid complement-mediated killing by sequestering fH to their surface 4 . Here we present the structure of a complement regulator in complex with its pathogen surface-protein ligand. This reveals how the important human pathogen Neisseria meningitidis subverts immune responses by mimicking the host, using protein instead of charged-carbohydrate chemistry to recruit the host complement regulator, fH. The structure also indicates the molecular basis of the host-specificity of the interaction between fH and the meningococcus, and informs attempts to develop novel therapeutics and vaccines.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Antigens, Bacterial - chemistry / Antigens, Bacterial - metabolism / Bacterial Proteins - chemistry / Bacterial Proteins - metabolism / Bacteriology / Binding Sites / Biological and medical sciences / Carbohydrates / Carbohydrates - chemistry / Complement (Immunology) / Complement Factor H - chemistry / Complement Factor H - immunology / Complement Factor H - metabolism / Crystallography, X-Ray / Fundamental and applied biological sciences. Psychology / Health aspects / Humanities and Social Sciences / Hydrogen bonds / Immune response / Immune system / letter / Ligands / Microbiology / Microorganisms / Models, Molecular / Molecular Mimicry / multidisciplinary / Neisseria meningitidis / Neisseria meningitidis - chemistry / Neisseria meningitidis - immunology / Neisseria meningitidis - metabolism / Nuclear Magnetic Resonance, Biomolecular / Pathogenicity, virulence, toxins, bacteriocins, pyrogens, host-bacteria relations, miscellaneous strains / Pathogens / Physiological aspects / Protein Binding / Protein Conformation / Proteins / Science / Science (multidisciplinary) / Structure-Activity Relationship / Substrate Specificity / Vaccines